Cyclic nucleotides and calcium are the principal second messengers of the signal transduction pathways within an area of the brain known as the basal ganglia or striatum. NMDA-type glutamate receptor activation and/or dopamine D2 receptor activation result in increased intracellular calcium concentrations (Greengard, P. et al. 1999. Neuron 23:435-447; Kotter, R. 1994. Prog. Neurobiol. 44:163-196), leading to activation of effectors such as calmodulin-dependent kinase II (CaMKII) and calcineurin and potentially to activation of calcium and calmodulin-dependent phosphodiesterases (CaM-PDEs). Dopamine D1 or D2 receptor activation leads to adenylyl cyclase activation (and increased cAMP) or inhibition (and decreased cAMP), respectively. Intracellular concentration of cGMP also are increased after dopamine D1 receptor activation and are unchanged or inhibited after D2 receptor activation. Cyclic nucleotides activate protein kinase A (PKA; cAMP-dependent protein kinase) and/or protein kinase G (PKG; cGMP-dependent protein kinase) that phosphorylate downstream signal transduction pathway elements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP responsive element binding protein (CREB). These signaling pathways are down-regulated by phosphodiesterases (PDEs) by hydrolysis of the cyclic nucleotides to their 5′-monophosphates. Calcium-regulated PDEs that hydrolyze cAMP and/or cGMP are therefore potential interfaces between dopamine-regulated and other intracellular signaling pathways in the basal ganglia (striatum), including but not limited to nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP) and endorphin intracellular signaling pathways.
Long-term potentiation and long-term depression, the major forms of plasticity associated with hippocampally-mediated learning and memory, are also regulated by the cyclic nucleotide and calcium/calmodulin signal transduction cascades, including the activity of PKA (Abel, T. et al. 1997. Cell 88:615-626; Skoulakis, E. M. C. et al. 1993. Neuron 11:197-208), CaMKII (Bach, M. E. et al. 1995. Cell 81:905-915; Mayford, M. et al. 1995. Cell 81:891-904), CREB (Bourtchuladze, R. et al. 1994. Cell 79:59-68; Guzowski, J. F. et al. 1997. Proc. Natl. Acad. Sci. USA 94:2693-2698; Yin, J. C. P. et al. 1994. Cell 79:49-58), and calcineurin (Mansuy, I. M. et al. 1998. Cell 92:39-49). Drosophila mutants have shown altered intracellular levels of cAMP or an altered cAMP signaling pathway with concomitant learning deficits in an olfactory conditioning paradigm (Qui, Y. and R. L. Davis. 1993. Genes Dev. 7:1447-1458; Livingstone, M. S. et al. 1984. Cell 37:205-215; Skoulakis, E. M. C. et al. 1993. Neuron 11:197-208; Davis, R. L. et al. 1995. Mol. Cell. Biochem. 149/150:271-278). The activity of cGMP has also been implicated in learning and memory through the nitric oxide pathway of retrograde signal transduction (Gaily, J. A. et al. 1990. Proc. Natl. Acad. Sci. USA 87:3547-3551; Garthwaite, J. 1991. Trends Neurosci. 14:60-67).
Ten families of PDEs have been identified but only Family I, the calmodulin-dependent phosphodiesterases (CaM-PDEs) have been shown to act as a potential point of interaction between the calcium and cyclic nucleotide signaling pathways. The three known CaM-PDE genes, PDE1A, PDE1B, and PDE1C, are all expressed in central nervous system tissue. PDE1A is expressed throughout the brain with higher levels of expression in the CA1 to CA3 layers of the hippocampus and cerebellum and at a low level in the striatum (Borisy, F. F. et al. 1992. J. Neurosci. 12:915-923; Yan, C. et al. 1994. J. Neurosci. 14:973-984). PDE1B is predominately expressed in the striatum, dentate gyrus, olfactory tract and cerebellum and its expression has been correlated with brain regions having high levels of dopaminergic innervation (Furuyama, T. et al. 1994. Mol. Brain. Res. 26:331-336; Polli, J. W. and R. L. Kincaid. 1994. J. Neurosci. 14:1251-1261; Yan, C. et al. 1994. J. Neurosci. 14:973-984). PDE1C is primarily expressed in olfactory epithelium, cerebellar granule cells, and striatum (Yan, C. et al. 1995. Proc. Natl. Acad. Sci. USA 92:9677-9681; Yan, C. et al. 1996. J. Biol. Chem. 271:25699-25706). While expression patterns have been extensively studied, a physiological role for the CaM-PDEs in the brain has not been established.
Therefore, there is a need in the art to provide new methods of screening that can be used to develop novel compositions or drugs that can be used to treat diseases or disorders related to the regulation of phosphodiesterases in the nervous system. Furthermore, there is a need to develop treatments for such diseases or disorders that are due, at least in part, to an aberration or dysregulation of an intracellular signaling pathway regulated by phosphodiesterases. The present invention provides such methods and compositions.
Citation or identification of any reference in Section 2, or in any other section of this application, shall not be considered an admission that such reference is available as prior art to the present invention.